We have attempted to elucidate the mechanisms of the neuropathogenesis of HIV-1 infection. We have investigated the interaction between HIV-1 and cerebellar granule cells in culture using two HIV isolates from AIDS patients with and without overt neurological symptoms. Upon exposure to HIV-1, progressive disruption of neuronal network and destruction of cells occurred in a time- and virus-dose-dependent manner. Immunostaining revealed that only neurons, not astrocytes or other proliferating cells, are killed. Viral proteins and HIV-1-specific DNA and RNA were detected in the culture of cerebellar neurons. HIV-1 isolates from the brain of an AIDS dementia patient is consistently more potent than other isolates from patients with immunological disease. This is the first evidence that cultured neuron is a direct target for HIV-1. In addition, we have preliminary results showing that three protein species isolated from various plants have anti-HIV-1 activity when tested in human peripheral blood lymphocyte systems.